TISSUE-REPAIR RESPONSE AS A FUNCTION OF DOSE DURING TRICHLOROETHYLENEHEPATOTOXICITY

Trichloroethylene (TCE), a widely used organic solvent and degreasing agent, is regarded as a hepatotoxicant. The objective of the present s tudies was to investigate whether the extent and timeliness of tissue repair has a determining influence on the ultimate outcome of hepatoto xicity, Male Sprague-Dawley rats (200-250 g) were injected with a 10-f old close range of TCE and hepatotoxicity and tissue repair were studi ed during a time course of 0 to 96 h, Light microscopic changes as eva luated by H&E-stained liver sections revealed a dose-dependent necrosi s of hepatic cells. Maximum liver cell necrosis was observed at 48 h a fter the TCE administration. However, liver injury as assessed by plas ma sorbitol dehydrogenase (SDH) showed a dose response over a 10-fold dose range only at 6 h, whereas alanine aminotransferase (ALT) did not show a dose response at any of the time points studied. A low dose of TCE (250 mg/kg) showed an increase in SDH at all time points up to 96 h without peak levels, whereas higher doses showed peak only at 6 h, At later time points SDI-P declined but remained above normal. In vitr o addition of trichloroacetic acid, a metabolite of TCE to plasma, dec reased the activities of SDH and ALT indicating that metabolites forme d during TCE toxicity may interfere with plasma enzyme activities in v ivo. This indicates that the lack of dose-related increase in SDH and ALT activities may be because of interference by the TCE metabolite. T issue regeneration response as measured by [H-3]thymidine incorporatio n into hepatocellular nuclear DNA was stimulated maximally at 24 h aft er 500 mg/kg TCE administration. A higher dose of TCE led to a delay a nd diminishment in [H-3]thymidine incorporation. At a low dose of TCE (250 mg/kg) [H-3]thymidine incorporation peaked at 48 h and this could be attributed to very low or minimal injury caused by this dose, With higher doses tissue repair was delayed and attenuated allowing for un restrained progression of liver injury. These results support the conc ept that the toxicity and repair are opposing responses and that a dos e-related increase in tissue repair represents a dynamic, quantifiable compensatory mechanism. (C) 1998 Society of Toxicology.